Improvement of acarbose production in Actinoplanes sp. SE50/110 by genetic engineering of the acarbose biosynthesis gene cluster

Background Actinoplanes spp. are Gram-positive aerobic bacteria producing a variety of pharmaceutically relevant substances such as antibacterial or antifungal agents. The most prominent product of these species is the α-glucosidase-inhibitor acarbose used for treatment of type-2 diabetes mellitus. The acarbose production strain is a derivative of the wild-type strain Actinoplanes sp. SE50/110 (ATCC 31042) generated by a classical mutation process. The deciphered genome sequence of Actinoplanes sp. SE50/110 wildtype strain (Schwientek et al. 2012) was the basis for developing the full branch of 'omics'-technologies for Actinoplanes, such as transcriptomics (Schwientek et al. 2014), proteomics (Wendler et al. 2013, 2015) and metabolomics (Wendler et al. 2014).

Aims of the project:
Recently, methods for genetic engineering of Actinoplanes sp. SE50/110 were developed. The first method in Actinoplanes sp. makes use of the ReDirect system, which was developed by Gust et al. in 2002 and used for directed mutations in Streptomyces coelicolor. As an alternative method the CRISPR-Cas9 system adapted for genetic engineering of actinomycetal genomes (Tong et al. 2015), could also be applied for Actinoplanes. The goal of this Ph.D. project is now to improve acarbose production in Actinoplanes sp. SE50/110 by using these established genetic engineering techniques. Possible targets for the improvement of acarbose biosynthesis of Actinoplanes sp. SE50/110 are the acarbose biosynthesis genes, which were found to be organised in one gene cluster (Wehmeier & Piepersberg, 2004). Duplications of single or multiple acarbose biosynthesis genes e.g. may result in an improvement of acarbose production. The phenotype of interesting genetically engineered production strains should be characterized in detail by applying 'omics'-technologies recently established for Actinoplanes.

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